P724: UPDATED SUBSTUDY RESULTS FOR IVOSIDENIB IN IDH1-MUTANT RELAPSED/REFRACTORY MYELODYSPLASTIC SYNDROME
Authors: Courtney Dinardo, Gail Roboz, Justin M. Watts, Yazan Madanat, Gabrielle T Prince, Praneeth Baratam, Stéphane de Botton, Anthony Stein, James M Foran, Martha L Arellano, David Sallman, Dylan M Marchione, Xiaofei Bai, Prapti A Patel, Stephanie M Kapsalis, Guillermo Garcia-Manero, Amir Fathi
Journal: HemaSphere (2023)

Background: Outcomes are poor and no therapies currently exist for patients (pts) with isocitrate dehydrogenase 1-mutant (mIDH1) relapsed/refractory myelodysplastic syndrome (R/R MDS) following hypomethylating agent (HMA) failure. In the first-in-human study of ivosidenib (IVO) in pts with advanced mIDH1 hematologic malignancies, 12 pts with R/R MDS received IVO 500 mg daily; the objective response rate (ORR), defined as complete remission (CR) + marrow CR (mCR) + partial remission (PR) was 75%, and the median response duration was 21.4 months. Following FDA Breakthrough Therapy designation for mIDH1 R/R MDS, the study was amended to expand R/R MDS enrollment. Aims: This phase I, open-label multinational substudy is evaluating the safety, tolerability, and clinical activity of IVO in pts with mIDH1 R/R MDS. The primary efficacy endpoint is the CR+PR rate; secondary endpoints include duration of CR plus PR, duration of transfusion independence, and time to transfusion independence. Methods: Pts aged ≥18 years with mIDH1 R/R MDS following standard-of-care therapy were enrolled. Oral IVO 500 mg was administered daily d1–28 in 28-day cycles until hematopoietic stem cell transplantation, progression, unacceptable toxicity, or another prespecified stopping criterion. Results: As of 26 Sep 2022, 19 pts had been enrolled (78.9% with HMA failure). Median IDH1 variant allele frequency was 19.7%. Please see Table 1 for more patient/disease characteristics. Median treatment duration was 9.26 (range: 3.3, 78.8) months. Treatment-related adverse events (TRAEs) occurred in eight (42.1%) pts, including a grade 1 corrected QT interval increase (n=1; 5.3% of pts), grade 3 fatigue (n=1), and grade 3 hyponatremia (n=1). Three pts (15.8%) experienced serious TRAEs: two (10.5%) pts with grade 2 differentiation syndrome (DS) and one (5.3%) pt with grade 2 rash and knuckle skin infection. No TRAEs led to permanent discontinuation of IVO. In the efficacy analysis set (N=18), CR and ORR rates were 38.9% and 83.3%, respectively. No PRs were observed. Eight (44.4%) pts experienced mCR, four (50.0%) of whom had hematologic improvement (HI) in ≥1 lineage (erythroid, platelet, and/or neutrophil). Of the red blood cell (RBC) and platelet transfusion-dependent pts at baseline, 71.4% and 75.0%, respectively, became transfusion independent (TI; no transfusion during ≥56 days). Of the RBC- and platelet-TI pts at baseline, 81.8% and 100%, respectively, remained TI at data cut off. Median time to CR was 1.87 (range: 1.0, 5.6) months. Kaplan-Meier estimates of median CR and OS duration were not reached (range: 1.9, 80.8*) and 35.7 (range: 3.7*, 88.7*) months, respectively, with * denoting a censored observation. One (5.6%) pt underwent stem cell transplant; two (11.1%) progressed to acute myeloid leukemia. Twelve (63.2%) pts remained alive at data cut off. Summary/Conclusion: IVO induced durable remissions, including a substantial proportion of CRs, with an acceptable safety profile in pts with mIDH1 R/R MDS, providing an effective treatment option for this molecularly defined subset. DS was uncommon and manageable. High proportions of pts became or remained TI, and HI was observed in half of the pts in mCR.Keywords: Myelodysplastic syndrome